Both dysmenorrhea and premature labor affect significant numbers of American women; however, treatment regimens are still lacking for both conditions. Dysmenorrhea, menstrual cramps, affects on average over 50% of women and results in frequent absenteeism or loss of activity. Andersch, B., Milsom I., An Epidemiologic study of young women with dysmenorrhea, A.J.O.G., 144:655-60 (1982). Young women report a somewhat higher incidence of dysmenorrhea than the average, with estimates ranging from 67% to 72%. Harlow, S. D., Parck M., A longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women, Br. J. Obstet. Gynaecol., 103:1134-42 (1996). Severe pain has been reported by 7 to 15% of women. Id.
In the United States alone an estimated 140 million work and school hours are lost per year due to this condition. Klein, J. R., Litt, I. F., Epidemiology of adolescent dysmenorrhea, Pediatrics, 68:6661-64 (1981). About 42% of United States university students between the ages of 17 and 19 have had to be absent from their daily activities at least once due to dysmenorrhea. Id. Approximately 15% of young women have one to three days of incapacitation each month and dysmenorrhea is the leading cause of short-term school absenteeism among adolescent young women. Id. This disease, with its constant regularity, results in notable social, educational, and economic losses in this country.
Dysmenorrhea consists of painful uterine cramping and is often accompanied by associated symptoms including nausea, vomiting, diarrhea, and lower backaches. Treatments for dysmenorrhea currently focus on the use of non-steroidal antiinflammatory drugs (NSAIDs). These drugs include, for instance, naproxen, ibuprofen, mefenamic acid, and meclofenamate sodium. Oral contraceptives are also used by some women in the treatment of dysmenorrhea. Despite the fact that these two regimens can be used together, the recurring problems of dysmenorrhea have not been eliminated for many women.
Specifically, the painful uterine cramping associated with dysmenorrhea is probably triggered by vasopressin and increased production of prostaglandins. The current method of treatment, with NSAIDs, blocks prostaglandin production and acts as a painkiller. Although this method of treatment is effective in some women and decreases symptoms in other women, researchers have wondered whether blocking the dysmenorrheic process at an earlier step would provide more effective treatment in the prevention of uterine cramping.
Although no link has formally been established, some researchers believe that untreated dysmenorrhea may play a role in the genesis of such serious clinical conditions as endometriosis. Recent studies have shown that endometriosis is associated with dyskinetic patterns of uterine contractions at the time of menses. Salamanca, A., Beltran, E., Subendometrial Contractility in Menstrual Phase Visualized by Transvaginal Sonography in Patients with Endometriosis. Fertil. Steril., 65:193-95 (1995). Additionally, the symptoms of dysmenorrhea can often mask the more serious disease of endometriosis. Symptoms of dysmenorrhea often occur in women with endometriosis for nearly ten years on average prior to laproscopic diagnosis of the later disease. Hadfield, R., Mardon, H., Barlow, D., Kennedy, S., Delay in the Diagnosis of Endometriosis: A Survey of Women from the U.S.A. and U.K. Human Reprod., 11:878-80 (1996).
Premature labor also affects a significant number of women in the United States. Preterm delivery is defined as delivery prior to 30 weeks of gestation. This phenomenon complicates 8 to 10% of births in the United States and is a leading cause of neonatal morbidity and mortality. Lockwood, C. J., The diagnosis of PTL and the prediction of preterm delivery, Clinical Obstetrics and Gynecology, Pitkin, R. M., Scott, J. R. (eds.), 38:675-678 (1995). In fact, prematurity causes 75% of perinatal deaths in this country. McCombs, J., Update on Tocolytic Therapy, Annals of Pharmacotherapy, 29:515-522 (1995). Premature infants also have an increased risk of other serious conditions, including respiratory distress syndrome, hyaline membrane disease, intracranial intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and have an increased incidence of cerebral palsy. Id.
Currently, preventing preterm delivery focuses on the early diagnosis of impending premature labor in women with intact membranes. Oral tocolytic agents, or uterine relaxants, are the treatment of choice. Tocolytic agents include progestational compounds, .beta.-adrenergic agonists, NSAIDs, calcium agonists, oxytocin, or vasopressin agonists, and potassium channel openers. The most widely used of these are the .beta.-adrenergic agonists such as terbutaline and ritodrine. It should be noted, however, that of the .beta.-adrenergic agonists, only ritodrine is approved by the F.D.A. for use in preterm labor. Other .beta.-adrenergic agonists, such as terbutaline, are approved for other conditions (e.g., asthma) but have been used by practitioners in the treatment of premature labor. As these drugs are given orally, however, treatment is accompanied by serious side effects. Research has failed to produce a .beta.-adrenergic agonist that is selective for the receptors in the uterus and consequently lacking of some of the most serious adverse events.
Terbutaline is a .beta.-adrenergic agonist. Its chemical formula is 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol. The empirical formula of terbutaline is C.sub.12 H.sub.19 NO.sub.3. Its molecular weight is 225.29. Its structural formula is as follows: ##STR1## Terbutaline, as a .beta.-adrenergic agonist, has been used primarily as a bronchodilator. .beta.-adrenergic agonists exert their pharmacologic effects by activation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of adenyl cyclase by .beta.-adrenergic agonists increases intracellular levels of cAMP. Cyclic AMP in turn reduces the availability of intracellular free Ca.sup.2+, which is required for the activation of myosin light-chain kinase, the enzyme that phosphorylates myosin and thereby allows it to combine with actin to form actomyosin. Lack of Ca.sup.2+ results in disruption of the actin-myosin interaction, with resultant inhibition of smooth muscle contractility. Due to their direct effects on smooth muscle contractility, .beta.-adrenergic agonists, such as terbutaline, may prove to be an effective therapy for both dysmenorrhea and premature labor.
In fact, oral and intravenous terbutaline has been used as a reasonably effective therapy for preterm labor. Studies have shown that oral or IV therapy can stop contractions or postpone delivery. Lyrenas, S., Grahnen, A., Lindberg, B., et. al., Pharmacokinetics of Terbutaline During Pregnancy, Eur. J. Clin. Pharmacol., 29:619-623 (1986); Berg., G., Lindberg, C., Ryden G., Terbutaline in the Treatment of Preterm Labour, Eur. J. Respir. Dis., 65:219-230 (1984). Adverse events can present significant problems in the treatment of preterm labor with terbutaline and are discussed further below.
A few studies also document the use of terbutaline in the treatment of dysmenorrhea. In one study, treatment with IV terbutaline inhibited myometrial activity, increased blood flow to the uterus, and relieved the pain occurring during uterine contractions accompanying dysmenorrhea. Akerlund, M., Andersson, K. E., and Ingemarsson, E., Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow, and Lower Abdominal Pain in Women with Primary Dysmenorrhoea, Br. J. of Obstet. & Gyn., 83(9):673-78 (1976). Terbutaline inhalers have even been evaluated for the treatment of dysmenorrhea. Kullander, S., Svanberg, L., Terbutaline Inhalation for Alleviation of Severe Pain in Essential Dysmenorrhea, Acta Obstet. Gynecol. Scand., 60:425-27 (1981). This therapy did provide some efficacy; however, treatment was not sufficient for most patients, who had to supplement with other medications for adequate relief. Further, the effect of each spray lasted as little as 1 hour. Id. One other .beta.-adrenergic agonist, salambutol, showed pain relief when administered intravenously. Lalos, O., Joelsson, I., Effect of Salbutamol on the Non-Pregnant Human Uterus In Vivo, Acta Obstet. Gynecol. Scand., 60:349-52 (1981).
Several problems with administration and adverse effects, however, prevent women affected by dysmenorrhea and premature labor from being able to take full advantage of this therapy. First, .beta.-adrenergic agonists such as terbutaline have a low bioavailability after oral administration. These pharmaceuticals are well absorbed but have extensive first-pass sulphation. Bioavailability has been estimated at between 15 and 20%. Concomitant food intake additionally decreases bioavailability by a further 30%. Bricanyl: Scientific brochure, Astra France Laboratories (1993).
Second, adverse effects significantly limit the current utility of terbutaline in the treatment of preterm labor and dysmenorrhea. Placental transfer of .beta.-adrenergic agonists such as terbutaline is relatively rapid; thus, adverse effects are observed in the fetus and neonate while treating premature labor using oral administration. Morgan, D. J., Clinical Pharmacokinetics of .beta.-Agonists, Clin. Pharmacokin., 18:270-294 (1990). Thus, when treating preterm labor, adverse events can affect not only the woman but also her child.
The most serious adverse events are cardiovascular in nature. Intravenous administration of terbutaline has been associated with palpitations and peripheral tremors. Akerlund, M., Andersson, K. F., Ingemarsson, I., Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow and Lower Abdominal Pain in Women With Primary Dysmenorrhea. Br. J. Obstet. Gyncol., 83:673-78 (1976). As a sympathomimetic amine, terbutaline can cause problems in patients with cardiovascular disorders (including arrhythmia, coronary insufficiency and hypertension), as well as with patients with hyperthyroidism, diabetes mellitus, or a history of seizures. Significant adverse reactions have been reported following administration of terbutaline to women in labor including pulmonary edema and hypoglycemia in the mother and or neonate child. Intravenous terbutaline has also been reported to aggravate preexisting diabetes and ketoacidosis. Other adverse events include: tremors, nervousness, increased heart rate, palpitations, and dizziness. Less frequent adverse effects include headaches, drowsiness, vomiting, nausea, sweating, muscle cramps, and ECG changes.
These adverse effects have precluded the use of .beta.-agonists such as terbutaline to prevent or treat dysmenorrhea as it considered to be a benign or non-threatening condition. Akerlund, M., Andersson, K. E., and Ingemarsson, E., Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow, and Lower Abdominal Pain in Women with Primary Dysmenorrhoea, Br. J. of Obstet. & Gyn., 83(9):673-78 (1976). Further, the risks involved have limited the use of these pharmaceutical agents in the treatment of preterm delivery and premature labor as the benefits must be balanced carefully against the seriousness of the adverse events involved.
In an attempt to address the severity of the adverse events involved, researchers have been attempting to identify another effective means for administering the drug that would decrease the risk involved. It is known that terbutaline can be administered directly to the uterus, resulting in preferential local concentrations as compared to peripheral circulation concentrations. Kullander et al. studied the correlation between the uterine and blood concentrations of terbutaline after insertion of a terbutaline-impregnated polymer ring (10% terbutaline sulfate in a 5 g vaginal ring), terbutaline in a cellulose gel (0.1 mg in 1 mL cellulose gel), or a placebo ring in a patient 24 hours before hysterectomy. Kullander, S., Svanberg, L., On resorption and the effect of vaginally administered terbutaline in women with premature labor. Acta. Obstet. Gynecol. Scand., 64:613-16 (1985). The methods followed in this reference, however, have distinct disadvantages. The water soluble cellulose-gel used can wash away and the use of a polymer ring can be uncomfortable and unpalatable for the woman, and thus both are distinctly disadvantageous.
Other pharmaceutical compounds with problematic adverse events have been successfully administered locally. The bioadhesive carrier of the present invention has been used in other drug delivery systems, although with different results than in the present invention. For example, polycarbophil is a main ingredient in the vaginal moisturizer Replens.RTM.. It has also been used as a base for compositions with other active substances such as progesterone (Crinone.RTM.) (see U.S. Pat. No. 5,543,150) and Nonoxynol-9 (Advantage-S) (see U.S. Pat. No. 5,667,492).
Additionally, it is important that pharmaceutical compositions do not interfere with all contractions and the homeostasis of menstruation. As menstrual blood does not clot, normal, regularized contractions are helpful to stop the bleeding. If there are no contractions, then the patient may not stop bleeding and may hemorrhage. Thus, it is an object of the invention to interfere with the dyskinetic contractions causing dysmenorrhea, without stopping contractions entirely.